Lyme disease is caused by the spirochete Borrelia burgdorferi. This zoonosis is the most prevalent vector borne infectious disease in the United States and Europe and its incidence is growing. The enzootic cycle of this pathogen requires that Ixodes spp. acquire B. burgdorferi from infected wildlife reservoirs and transmit it to other uninfected wildlife. At present, there are no effective measures to control B. burgdorferi;there is no human vaccine available, and existing vector control measures are generally not acceptable to the public. However, if B. burgdorferi could be eliminated from its reservoir hosts or from the ticks that feed on them, the enzootic cycle would be broken, and the incidence of Lyme disease would decrease. We have developed a reservoir targeted vaccine (RTV) based on the immunogenic outer surface protein A (OspA) of B. burgdorferi aimed at breacking the natural cycle of this spirochete. White-footed mice (Peromyscus leucopus), a major reservoir species for this spirochete in nature, develop a systemic anti-OspA IgG response after vaccination, that is protective against B. burgdorferi infection upon tick challenge and clears B. burgdorferi from the tick vector (90% efficacy in the laboratory). In addition, we performed a pilot field study and determined that ingestion of this bait vaccine by P. leucopus induced a high titer of anti-OspA antibodies that blocked transmission of B. burgdorferi to the next tick cohort. The main goal of this UO1 proposal is to optimize the immunization parameters of our OspA-based RTV for P. leucopus in the laboratory, and to determine its efficacy in reducing the density of B. burgdorferi-infected ticks, and thus human Lyme disease risk, in the field.